Pharmacogenetics of drug metabolizing enzyme: thiopurine methyl transferase phenotypes and multidrug resistance 1 gene polymorphism in inflammatory bowel disease.

Abstract

Inflammatory bowel disease(IBD) is progressing rapidly in developing countries such as Iran. This research is intended to compile the frequency distribution of the drug metabolizing enzyme, thiopurine methyl transferase(TPMT) and the drug transporter, Multi drug resistance(MDR1) which are involved in metabolism of many therapeutics such as thiopurines in inflammatory bowel disease(IBD). Ethnicity is an important variable influencing drug response. The aims of this research were to investigate the association of TPMT phenotypes with MDR1 genotypes. TPMT activity was measured by using a non-extraction HPLC method and genotype for the C3435T polymorphism of MDR1 gene was determined in 215 unrelated IBD patients including of 85 males and 130 females and 212 unrelated healthy individuals consisted of 96 males and 116 females as control group by PCR-RFLP in Iran's western population. TPMT phenotypes demonstrated no frequency for deficient, 2.2% for low and 97.8% for normal activity that is different with results of other studies. Interestingly there were a significant negative correlation between TPMT activities as calculated based on nmol/grHb/h and positive correlation calculated in mU/L with Hb levels in IBD patients and control subjects. Dominant and codominant MDR1 C3435T gene polymorphism increased the risk of IBD by 1.45 and 1.46 times, respectively. IBD patients with MDR1 mutant genotypes C3435T, had lower TPMT activites and Hb concentrations. Using of mU/L is more appropriate than nmol6MTG/grHb/h for expressing TPMT activity. TPMT frequency of deficient and low activity in western Iran is low. The carriers of mutant C3435T MDR1 are not good TPMT methylators.